TITLE PAGETitle of the article.

Systematic review and evidence synthesis of non-cervical human papillomavirus-related disease health systems costs and quality of life estimates.

Full name, postal address, e-mail and telephone number of the corresponding author.

Corresponding authorFull name Koh Jun OngPostal address Centre for Infectious Disease Surveillance and Control

National Infection ServicePublic Health England61 Colindale Avenue,London NW9 5EQ,United Kingdom

E-mail kohjun.ong@phe.gov.ukTelephone number 0208 327 6739Highest academic degrees MSc

Full name, department, institution, city and country of all co-authors.

Co-author 1Full name Marta ChecchiDepartment, institution, city and country

National Infection Service, Public Health England, London, United Kingdom

Highest academic degrees MScCo-author 2Full name Lorna BurnsDepartment, institution, city and country

Peninsula Schools of Medicine and Dentistry, University of Plymouth, Plymouth, Devon, United Kingdom

Highest academic degrees MScCo-author 3Full name Charlotte PavittDepartment, institution, city and countryHighest academic degrees MScCo-author 4Full name Maarten J PostmaDepartment, institution, city and country

i. Department of Pharmacy, University of Groningen , Groningen, Netherlands

ii. Department of Health Sciences, University Medical Center Groningen, Groningen, Netherlands

iii. Department of Economics, Econometrics & Finance, University of Groningen, Groningen, Netherlands

Highest academic degrees PhD

1

Co-author 5Full name Mark JitDepartment, institution, city and country

i. National Infection Service, Public Health England, London, United Kingdom

ii. Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom

Highest academic degrees PhD

Word count, excluding title page, abstract, references, figures and tables.

Abstract 298 of 300 max.Main text 2,322 of 3,000 max.Number of figures and tables 3 Figures and 1 Table

2

KEYWORDSPapillomaviridaecosts and cost analysismeta-analysissystematic reviewCondylomata Acuminatarecurrent respiratory papillomatosisanus neoplasms head and neck neoplasms penile neoplasms vulvar neoplasmsvaginal neoplasms

AUTHORS’ CONTRIBUTIONSKJO, MJP, and MJ conceived and planned the systematic review. LB conducted the systematic literature searches. KJO, MC, and CP, carried out sifting and data extraction of the systematic literature search results. KJO conducted the meta-analysis and took the lead in writing the manuscript, with guidance from MJP and MJ. All authors provided critical feedback on the manuscript.

CORRESPONDING AUTHOR STATEMENTThe Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in STI and any other BMJPGL products and sub-licences such use and exploit all subsidiary rights, as set out in our licence

http://group.bmj.com/products/journals/instructions-for-authors/licence-forms

3

ABSTRACT

BACKGROUND

Many economic evaluations of human papillomavirus (HPV) vaccination consider multiple disease

outcomes in addition to cervical cancer, including anogenital warts, recurrent respiratory

papillomatosis, and anal, oropharyngeal, penile, vulvar and vaginal cancers. However, these

evaluations mostly derive cost and utility parameters for these outcomes from single studies or

informal rapid literature reviews.

METHODS

We conducted a systematic review of articles up to June 2016 to identify costs and utility estimates

admissible for an economic evaluation from a single-payer health care provider’s perspective. Meta-

analysis was performed for studies that used same utility elicitation tools for similar diseases. Costs

were adjusted to 2016/17 US dollars.

RESULTS

Sixty one papers (35 costs; 24 utilities; 2 costs and utilities) were selected from 10,742 initial records.

Cost per case ranges were US$124–US$883 (anogenital warts), US$6,912–US$52,579 (head and neck

cancers), US$12,936–US$51,571 (anal cancer), US$17,524–34,258 (vaginal cancer), US$14,686–

28,502 (vulvar cancer), and US$9,975–27,629 (penile cancer). Total cost for 14 adult RRP patients

was US$137,601 (1 paper).

Utility per warts episode ranged from 0.651–1 (12 papers, various utility elicitation methods), with

pooled mean EQ-5D and EQ-VAS of 0.86 (95% CI 0.85–0.87) and 0.74 (95% CI 0.74–0.75),

respectively. Fifteen papers reported utilities in head and neck cancers, with range across studies of

0.29 to 0.94. Mean utility reported ranged from 0.5 to 0.65 (anal cancer; range across studies), 0.59

(0.54–0.64) (vaginal cancer), 0.65 (0.60–0.70) (vulvar cancer), and 0.79 (0.74–0.84) (penile cancer).

4

CONCLUSIONS

Differences in values reported from each paper reflect variations in cancer site, disease stages, study

population, treatment modality/setting, and utility elicitation methods used. As patient management

changes over time, corresponding effects on both costs and utility need to be considered to ensure

health economic assumptions are up-to-date and closely reflect the case-mix of patients.

5

KEY MESSAGES

This systematic review identified 61 papers (35 costs; 24 utilities; 2 costs and utilities) reporting

economic parameters for HPV-related non-cervical diseases.

Differences in cost and utility estimates arise from study population, disease stage, cancer type,

treatment strategies and country perspective taken.

Authors of economic evaluations need to consider economic parameter assumptions to ensure

they accurately reflect the timing and perspective of the population considered.

6

INTRODUCTION

Almost a hundred economic evaluations of human papillomavirus (HPV) vaccination had been

published by June 2016[1–3]. Initially most of these analyses focused on the health and economic

benefits of HPV vaccination in preventing cervical cancer and its precursors, since these were the

only cancer outcomes listed in the initial licensure indication for the first two licensed HPV vaccines

(the bivalent vaccine Cervarix and the quadrivalent vaccine Gardasil)[4,5]. More recently, evidence

has emerged of other diseases that are potentially HPV vaccine-preventable, including recurrent

respiratory papillomatoses (RRP) and non-cervical cancers such as vulvar, vaginal, anal, penile, and

head and neck cancers[6,7]. Although attributable risk of HPV in each of these non-cervical cancers

varies[7], these outcomes are important to incorporate into cost of illness studies of HPV-related

diseases and economic evaluation of HPV vaccination for two reasons: (i) they give a comprehensive

picture of the (direct and indirect) benefits of introducing HPV vaccination, and (ii) they are the key

drivers of comparative evaluations of different strategies for vaccination, such as gender-neutral

compared with female-only vaccination and the choice between nonavalent, quadrivalent and

bivalent vaccination.

Economic evaluations require input parameters in terms of the costs and disutilities (measured in

units such as quality adjusted life years or QALYs) for different disease outcomes. To our knowledge,

most published economic evaluations to date have relied on data from the authors’ own knowledge

or from informal rapid reviews of the literature. Additionally, there exist a number of systematic

reviews (without quantitative evidence synthesis) conducted before 2013 covering quality of life for

specific diseases such as anogenital warts[8] and head and neck cancers[8–11] but none known of in

more recent years covering a wider range of non-cervical HPV-related diseases on both costs and

utilities. This gap in the literature may have led to bias in published economic evaluations because

they may have failed to consider the entirety of the literature in their parameter estimates.

7

To address this shortcoming, we have conducted a systematic review to compile and summarise

costs and quality of life (utility) estimates relevant to HPV-related diseases apart from cervical

cancer. We have selected studies that would be admissible for an economic evaluation from the

perspective of a single-payer health care provider such as the reference case used by the National

Institute for Health and Care Excellence (NICE) in the United Kingdom[12].

8

METHODS

Search Methods

A search of the databases Ovid Medline, Embase, Cinahl, Scopus and NHS Economic Evaluations

Database was performed in June 2016. The search strategy combined terms for HPV-related

diseases with health economics terms. HPV-related disease terms included both free text and, where

available, subject headings for the following (ICD-10 codes in parentheses): anogenital warts – AGW

(A63.0), recurrent respiratory papillomatosis – RRP (D14), cervical cancer (C53), vulvar cancer (C51),

vaginal cancer (C52), anal cancer (C21), penile cancer (C60), oropharyngeal cancer (C09 and C10),

oral cavity cancer (C01 to C05) – including cancer of the tonsil, laryngeal cancer (C32), and head and

neck cancer as a general term included for completeness, recognising that not all head and neck

cancers are HPV-attributed. Health economics terms included terms for health utilities/disutilities,

costs, quality of life, quality of life instruments (e.g. EQ-5D) and measurement methods such as time-

trade off (TTO) and standard gamble (SG). Results were limited to peer-reviewed full research

articles in the English language only. Inclusion criteria covered all papers on HPV-related diseases

costs and/or disutilities from high-income countries as defined by the Organisation for Economic

Cooperation and Development, stated in Appendix 1[13].

Details of the full search strategies used are provided in Appendix 1.

Result Screening

Screening was undertaken from September to December 2016. The initial 10,742 articles identified

were independently single screened based on titles and abstracts to identify potentially relevant

papers (KJO, MC, CP). Allocation decisions at this stage were done leniently, with titles that were

uncertain marked for a further round of screening. The 2,785 references selected were entered into

another round of single screening (KJO, MC, CP), whereby the results were reconsidered and

categorised by type (cost or disutility) and disease area.

9

Although the objective of this systematic review focused on non-cervical diseases, for completeness,

the search strategy and first two stages of single screening included cervical precancer/cancer.

Selected titles for cervical precancer/cancer can be made available to interested researchers.

Selection criteria

Once titles from the second single screen had been identified, full-text papers were proportionately

distributed to each reviewer (KJO, MC, CP) for the final round of paper selection and data extraction.

For HPV-related disease management costs we included only papers that took the perspective of a

health care provider from a country with universal healthcare system (either Bismarck-type or

Beveridge-type). For utility estimates, any paper that reported on quality of life loss that was

reported on a scale from 0 to 1 and measured using either an indirect generic utility elicitation tool

such as the EuroQol EQ-5D, or one of the primary/direct methods such as time-trade off or standard

gamble were included. These criteria ensured that selected studies would be admissible for

economic evaluations in most single-payer health care jurisdictions (eg. the NICE reference

case[12]).

Data extraction

A standard form to collect the data was created. Relevant data extracted from the papers are

described in Appendix 2.

Data extraction was done by one reviewer and checked by a second reviewer, with discrepancies

resolved through discussion.

Data synthesis

A descriptive comparison of data extracted from different papers was made. Costs were adjusted to

2016/17 US dollars using the hospital and community health services inflation indices, with foreign

currencies converted to US dollars using historical Bank of England average exchange rates for a

10

reported year[14,15]. Quality of life values were presented separately for utility score and duration

of disutility, if reported in a paper.

Meta-analyses using random effect models were conducted for AGW utility estimates for papers

whereby utility estimates were generated using standard utility elicitation instruments, such that

outcomes measured were comparable. Meta-analyses were not conducted for utility weights of non-

AGW outcomes nor were they conducted for any cost estimates, given higher heterogeneity in how

costs were measured and the specific disease type and stages considered.

Software

References were collected in EndNote and transferred to Eppi-Reviewer 4 software (Thomas J,

Brunton J, Graziosi S, 2010) for screening. Final papers were captured in Mendeley Version 1.15.3.

Data extraction was collated in Microsoft Excel 2010. Meta-analysis was conducted in STATA13.

11

RESULTS

The initial search strategy identified 10,742 records after deduplication. Screening based on titles

and abstracts reduced these to 729 full-text papers that were reviewed. Of these, 61 papers were

selected. A PRISMA flow diagram is presented in .

Costs

A total of 37 papers reported non-cervical HPV-related disease management costs[16–52], about

half of which reported costs for AGWs[16–35]. Four papers reported costs for more than one

disease[26,30,36,37]. Management costs from studies differed by country, disease stages or

management settings used, and data collection method.

Figure 2 (Panel A) presents a summary of the various cost per case estimates, where presented, for

AGWs. Estimated cost per case of AGW ranged from US$124 per case in a patient seen for care in

Canada[25] to US$883 per case in Spain[34]. AGW management costs were derived from

information collected from case note reviews (13 papers)[18–22,25,26,28,29,31–34], expert opinion

(3 papers)[16,24,35], surveillance data (3 papers) [17,23,27] or the literature (1 paper) [30].

Cost per case reported for the various cancers is presented in Figure 2 (Panel B). Six papers reported

management cost for anal cancers[30,36–40], but half of these were annual treatment

costs[37,39,40] not cost per case. Cost per anal cancer case ranged from US$12,936 (Italy[30]) to

US$51,571 (Denmark[36]). Twelve reported head and neck cancer treatment costs and differed

depending on cancer site and stage[30,37,41–50], with costs ranging from US$6,912 (Laryngeal

cancer, T1 carcinoma, the Netherlands[48]) to US$52,579 (weighted average costs for cancers of the

oral cavity, larynx or oropharynx, the Netherlands[45]). There were four papers each that reported

cost for vaginal[26,30,36,37], vulvar[26,30,36,37], and penile[30,36,37,51] cancers, with cost ranges

of US$17,524–34,258, US$14,686–28,502, and US$9,975–27,629, respectively. Six papers only

12

presented total spend and/or annual spend for the non-cervical cancers[37,39,40,42,44,52], detailed

findings are reported in Appendix 2.

One paper reported on total treatment cost covering 14 adult patients seen for RRP care at a clinic in

Glasgow, Scotland, between January 2013 to April 2014 was reported at US$137,601[52].

Utilities

A total of 25 papers on health-related quality of life were identified (full reference list in Appendix 2)

[19,20,53–60;W1-W15]. Two of these covered multiple diseases[53,W15]. Fifteen papers covered

head and neck cancers, including oral and laryngeal cancers[53,W2–W15], whilst another 12 papers

reported on quality of life for AGWs[19,20,53–60,W1,W16].

Utility per case of AGW ranged from 0.651–1, depending on the method of utility elicitation used.

Utility values were generally higher when measured using EQ-5D, compared with Visual Analog Scale

(VAS), TTO, or SG methods used within a single study. Full details of study background and findings

are presented in Appendix 2. Meta-analyses of EQ-5D and EQ-VAS, from nine papers each, found

high heterogeneity (I-squared >90%) in the utility values reported (Figure 3). Pooled mean EQ-5D

and EQ-VAS were 0.86 (95% CI 0.85-0.87) and 0.74 (95% CI 0.74-0.75), respectively.

Methods used to elicit utility for HPV-related cancers included EQ-5D, EQ-VAS, HUI3 (Health Utility

Index Mark 3), TTO, SG, SF-36 (Short-Form 36), SF-6D (Short-Form Six-Dimension), and 15D. Utility

estimates for head and neck cancers differed depending on the utility elicitation method used to

generate utility scores, cancer site, patient age, the disease stage at point of completion of the

quality of life questionnaire, and treatment modality. For example, patients who had early stage oral

cancers completed utility questionnaires at a later point in time in Govers et al. [W3], whilst another

study by Loimu et al. [W7] was a prospective study where patients with laryngeal, pharyngeal or

nasal cavity carcinoma had their utility measured at month-0, 3, 6, and 12 after treatment initiation.

13

We present summary study details and key utility output presented in each of these 15 papers on

quality of life for HPV-related cancers in Table 1 with further details in Appendix 2.

14

TABLE

Table 1 Summary utility measurement and value ranges for HPV-

related non-cervical cancers

No

.

Author,

year

Cancer type;

notes

Country n Utility elicitation instrument used;

mean (unless otherwise specified)

values and/or ranges reported

1 Aro,

2016[W2]

Head and neck Finland 214 15D; 0.872

2 Govers,

2016[W3]

Oral; mean

years after

treatment

range 1.9 (SD

1.4, range 0.4-

4.1) to 5.2 (SD

3.2, range 0.4-

11.0)

The

Netherland

s

174 EQ5D; range 0.794 (SE 0.04) to 0.863

(SE 0.05)

EQVAS; range 69.7 (SE 3.7) to 79.6 (SE

4.8)

3 Pickard,

2016[W4]

Head and neck US 50 EQ5D; 0.828

EQVAS; 60.8

15

4 Rettig,

2016[W5]

Head and neck;

sites include

larynx, oral

cavity,

oropharynx,

hypopharynx,

nasopharynx,

and nasal

cavity/paranasa

l sinuses

US 165

3

SF6D; range 83.7 (95% CI 82.0, 85.4)

to 88.0 (95% CI 86.2, 89.7)

5 Kent,

2015[W6]

Oral cavity and

pharynx

US SF6D; 0.69 (95% CI 0.68, 0.70)

6 Loimu,

2015[W7]

Head and neck Finland 64 15D; range 0.829 (0.12) to 0.886

(0.10)

7 Noel,

2015[W8]

Head and neck Canada EQ5D; 0.82 (SD 0.18, range -0.07-1.0)

EQVAS; 0.76 (SD 0.19, range 0.2-1.0)

SG; 0.91 (SD 0.17, range 0.2-1.0)

TTO; 0.94 (SD 0.14, range 0.3-1.0)

HUI3; 0.75 (SD 0.25, range -0.06-1.0)

8 Pottel,

2015[W9]

Head and neck Belgium 81 EQ5D; median (Q1, Q3) range 0.29

(0.0, 0.76) to 0.66 (0.55, 0.76)

9 Lango,

2014[W10]

Head and neck US 159 EQ5D; median 85 (IQR: 70-90)

10 Nijdam,

2008[W11]

Head and neck The

Netherland

s

119 EQ5D; median 75

16

11 Rogers,

2006[W12]

Head and neck UK EQ5D; 0.75 (SE 0.02; range -0.18 - 1.0)

EQVAS; 74 (SE 1)

12 Ringash,

2000[W13]

Laryngeal Canada 84 TTO; 0.878 (SD 0.174; range 0.25 - 1)

13 Downer,

1997[W14]

Oral UK 100 SG; range 0.68 (SD 0.33) to 0.88 (SD

0.20)

14 Marcellusi,

2015[53]

Anal Italy 26 EQ5D; 0.6 (SD 0.3)

TTO; range 0.5 (SD 0.26; 95% CI 0.4-

0.61) to 0.52 (SD 0.25; 95% CI 0.36-

0.67)

Head and neck;

squamous cell

carcinoma

Italy 79 EQ5D; 0.8 (SD 0.2)

TTO; range 0.69 (SD 0.3; 95% CI 0.62-

0.75) to 0.59 (SD 0.3; 95% CI 0.46-

0.72)

15 Conway,

2012[W15]

Anal Australia 95 SG; 0.57 (95% CI 0.52 - 0.62); median

0.65 (IQR 0.45 - 0.75)

Oropharyngeal Australia 99 SG; 0.58 (95% CI 0.53 - 0.63); median

0.65 (IQR 0.45 - 0.75)

Vaginal Australia 98 SG; 0.59 (0.54 - 0.64); median 0.65

(IQR 0.45 - 0.75)

Vulvar Australia 98 SG; 0.65 (0.60 - 0.70); median 0.65

(IQR 0.45 - 0.85)

Penile Australia 97 SG; 0.79 (0.74 - 0.84); median 0.85

(IQR 0.65 - 1.0)

17

DISCUSSION

Statement of principal findings

This systematic review provides an updated and comprehensive summary of the cost and utility

evidence for non-cervical HPV-related diseases that can be used in economic evaluations conducted

from the perspective of a national health care provider. There appeared to be high heterogeneity in

the papers identified, in terms of disease stages, population studied, treatment modality and setting,

as well as utility elicitation methods used. The EuroQoL EQ-5D or EQ-VAS was commonly used in

AGWs and in at least half of the non-cervical cancers studies.

Whilst the evidence in terms of both costs and utility values appear to be abundant for AGWs, it is

less so for other cancers. This may reflect the fact that protection against AGWs is one of the main

differentiating factors between the two competing HPV vaccines (quadrivalent and bivalent) on the

market until licensure of the nonavalent vaccine in 2015, with several published economic

evaluations focusing on the difference in cost-effectiveness between the two vaccines[W17].

Strengths and weaknesses of the study

Many papers did not report a single overall cost or utility estimate for a disease episode. Instead,

they reported cost or utility values at different stages of the disease, which means that to obtain a

single overall figure over entire disease episode, further details about patient case mix and changes

in utility over time are needed. This includes a combination of treatment received at different stages

of disease. For example, Kim et al., 2011, reported post-operative management cost for a selective

group of head and neck cancer patients who had received surgical resection[43].

In addition, treatment modalities are likely to change over time, with corresponding effects on both

treatment costs and quality of life (due to changes in recovery time and patient experience). This

18

means that applying the same methodology to the same group of patients but managed differently

will likely return different costs and utility estimates.

The NICE-recommended utility elicitation method is EQ-5D completed by patients and scored using

population norms. This type of evidence is not always available. When alternative utility elicitation

methods are used, such as direct utility elicitation methods, their score can be quite different, as

demonstrated by Noel et al., 2015[68]. In their study, patients with upper aerodigestive tract cancer

completed five direct/indirect utility measures (EQ-5D, VAS, HUI3, standard gamble, and time trade-

off). The authors found that direct utility elicitation methods (SG and TTO) returned higher utility

scores, possibly due to patients being more risk-averse. When the SG method was used in another

study (Conway et al., 2012[W15]) completed by general population, the utility score for

oropharyngeal cancers was lower than head and neck cancers scored using SG in Noel et al.,

2015[68], although this could be due to the scenario descriptions used.

Meaning of the study: possible mechanisms and implications for

clinicians or policymakers

This systematic review highlights the importance of understanding the data source used in economic

evaluation, ensuring that health economic assumptions are up-to-date and closely reflect the case-

mix of patients considered in the analysis.

Unanswered questions and future research

During the paper screening and evaluation of eligibility stage, many papers on head and neck

cancers were identified but they often used SF-36 generic utility measures and reported two

summary scores covering physical and mental domains separately. Only four studies[56,59,W5,W6]

reported a single summary score and were included. To be most applicable to economic evaluations,

mapping exercises are needed to convert SF-36 values to single SF-6D scores specific to a country's

19

population. Future analyses could consider extracting findings from relevant papers and converting

to SF-6D scores, especially for diseases with insufficient utility estimates evidence.

Future research can also focus on identifying the duration of disutility to be applied to a disease,

since quality of life changes over time, and is an important component of the QALY calculations.

20

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31

FIGURE LEGEND

Figure 1 PRISMA flow diagram

32

Figure 2 Disease management costs reported in selected papers.

Panel A outlines costs reported for anogenital warts (AGWs).

Panel B contains an extraction of non-cervical cancer

management costs; Panel A: Cost per case of AGWs management

as reported in the relevant papers; Note that overall cost per

patient is presented where this information is available,

otherwise, cost per patient broken down by e.g. gender or

new/recurrences presented and these are specified; Herse et al.,

2011 not included as they presented minimum and maximum

total cost of all patients, not per patient; Cost per patient for

resistant cases reported in Hillemanns et al., 2008 not presented

on this figure; Panel B: Cost per case of cancer management;

Figure only presents cost per patient for their cancer

management, excluding where only annual costs were reported or

where total cost to the health care system was reported but not

per patient cost; Note: H&N=Head and neck; Preuss, 2007,

minimum and maximum costs reported for oropharyngeal

carcinomas treatment with surgery and postoperative

radio(chemo)therapy.

33

Figure 3 Forest plots of pooled mean (95% CI) of studies reporting

AGW EQ-5D (Panel A) and EQ-VAS (Panel B) utility estimates;

Panel A: Pooled AGW EQ-5D utility estimates; Panel B: Pooled

AGW EQ-VAS utility estimates. Note: utility estimates for different

subgroups within Vriend, 2014[54] and Drolet, 2011[56] were

pooled together and the combined mean and 95% CI were

subsequently added to utility estimates from the other studies to

generate an overall pooled mean and 95% CI.

34